Examining protein interactions that stabilize the structure and function of SERCA pumps in muscle

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Muscle cells in our body are often exposed to a variety of stressful conditions such as heat or oxidative stress or in association with a variety of diseases such as muscular dystrophy. When muscle cells are exposed to stress, the calcium level inside the cells increases and it is believed that cell damage and even cell death will occur as a result of the increased cellular calcium. One major reason for the increase in calcium with stress is that the enzyme responsible for maintaining normal calcium levels in muscle, namely the calcium pump, becomes damaged with stress. Therefore, it would be expected that cell damage would be reduced and survival would be increased after stress if the calcium pump could somehow be protected. We have established through our research that a naturally occurring protein in the body, called heat shock protein 70 (Hsp70), can protect the calcium pump in muscle during heat stress; however, we haven't figured out exactly how this works yet or whether other proteins normally found in muscle might also protect the calcium pump. One major, long-term objective of this program of research is to understand how Hsp70 and two other muscle proteins called phospholamban (PLN) and sarcolipin (SLN), interact with and protect the calcium pump under a wide range of conditions in both healthy and diseased muscle. For this objective, we will use genetically modified mice that either have higher than normal muscle levels of one of these proteins (Hsp70) or completely lack the protein(s) (PLN and/or SLN) and we will expose the muscle tissues to various types of stress (i.e. heat, low oxygen, oxidative stress) to determine if, and how, Hsp70, PLN and SLN can protect the calcium pump and preserve muscle function under those conditions. A second major objective this work addresses is understanding how PLN and SLN control calcium pumps and muscle contractile properties during transitions from rest to exercising conditions. Within one second of the onset of muscle contraction there are enhancements in both force producing and relaxation inducing properties of skeletal muscle but the mechanisms involved are not completely understood. We will use genetically modified mice to test the hypotheses that PLN and SLN play an important role in these classic properties of skeletal muscle. Overall, this basic research will build better understanding of the complex regulation of calcium pumps in muscle and the cellular mechanisms that exist to protect the structure and function of these vital muscle enzymes during stress. This work could have important implications that extend into a number of fields (i.e. cancer and heart disease research) because protecting the calcium pump could prevent increases in calcium and improve cell survival following stress and in certain diseases.